Propensity score-matched analysis of the short-term outcomes of robotic versus laparoscopic surgery for rectal cancer.

PURPOSE: The advantages of robot-assisted rectal surgery (RARS) over conventional laparoscope-assisted rectal surgery (LARS) remain controversial. This study was performed to compare the short-term outcomes of RARS and LARS. METHODS: We retrospectively analyzed data of 207 patients who had undergone either RARS (n = 97) or LARS (n = 110) for rectal cancer (RC) from 2018 to 2020. A 1:1 matched propensity score-matched analysis was performed and the surgical outcomes of the two groups compared. RESULTS: After matching, a well-balanced cohort of 136 patients was analyzed (n = 68 in each group), and there was no significant difference in the median operative time. The RARS group had less intraoperative blood loss than the LARS group. There were no significant differences in length of postoperative hospital stay or complication rate between the two groups. In the subgroup of lower RC, defined as the inferior edge of the tumor being within the rectum distal to the peritoneal reflection, the rate of sphincter preservation was higher in the RARS group (81.8% vs. 44.4%, p = 0.021). CONCLUSION: This study shows that RARS is a safe and feasible approach for RC compared with LARS, RARS having the advantage of more often preserving the sphincter.

Discovery of a Novel Series of Potent, Selective, Orally Available, and Brain-Penetrable C1s Inhibitors for Modulation of the Complement Pathway.

A novel series of non-amidine-based C1s inhibitors have been explored. Starting from high-throughput screening hit 3, isoquinoline was replaced with 1-aminophthalazine to enhance C1s inhibitory activity while exhibiting good selectivity against other serine proteases. We first disclose a crystal structure of a complex of C1s and a small-molecule inhibitor (4e), which guided structure-based optimization around the S2 and S3 sites to further enhance C1s inhibitory activity by over 300-fold. Improvement of membrane permeability by incorporation of fluorine at the 8-position of 1-aminophthalazine led to identification of (R)-8 as a potent, selective, orally available, and brain-penetrable C1s inhibitor. (R)-8 significantly inhibited membrane attack complex formation induced by human serum in a dose-dependent manner in an in vitro assay system, proving that selective C1s inhibition blocked the classical complement pathway effectively. As a result, (R)-8 emerged as a valuable tool compound for both in vitro and in vivo assessment.

Isolation of extended-spectrum ß-lactamase-producing Escherichia coli from Japanese red fox (Vulpes vulpes japonica).

Antimicrobial resistance is a global concern requiring a one-health approach. Given wild animals can harbor antimicrobial-resistant bacteria (ARB), we investigated their presence in 11 fecal samples from wild animals using deoxycholate hydrogen sulfide lactose agar with or without cefotaxime (CTX, 1 mg/L). Thus, we isolated CTX-resistant Escherichia coli from two Japanese red fox fecal samples. One strain was O83:H42-ST1485-fimH58 CTX-M-55-producing E. coli carrying the genes aph(3″)-Ib, aph(3')-Ia, aph(6)-Id, mdf(A), sitABCD, sul2, tet(A), and tet(B), whereas the other was O25:H4-ST131-fimH30 CTX-M-14-producing E. coli carrying mdf(A) and sitABCD and showing fluoroquinolone resistance. Thus, the presence of extended-spectrum ß-lactamase producers in wild foxes suggests a spillover of ARB from human activities to these wild animals.

Identification of α-Synuclein Proaggregator: Rapid Synthesis and Streamlining RT-QuIC Assays in Parkinson's Disease.

We report the discovery of two compounds, TKD150 and TKD152, that promote the aggregation of α-synuclein (aSN) using a real-time quaking-induced conversion (RT-QuIC) assay to detect abnormal aSN. By utilizing a Pd-catalyzed C-H arylation of benzoxazole with iodoarenes and implementing a planar conformation to the design, we successfully identified TKD150 and TKD152 as proaggregators for aSN. In comparison to a previously reported proaggregator, PA86, the two identified compounds were able to promote aggregation of aSN at twice the rate. Application of TKD150 and TKD152 to the RT-QuIC assay will shorten the inherent lag time and may allow wider use of this assay in clinical settings for the diagnosis of α-synucleinopathy-related diseases.

Quantitative Susceptibility Mapping: Basic Methods and Clinical Applications.

Quantitative susceptibility mapping (QSM), one of the advanced MRI techniques for evaluating magnetic susceptibility, offers precise quantitative measurements of spatial distributions of magnetic susceptibility. Magnetic susceptibility describes the magnetizability of a material to an applied magnetic field and is a substance-specific value. Recently, QSM has been widely used to estimate various levels of substances in the brain, including iron, hemosiderin, and deoxyhemoglobin (paramagnetism), as well as calcification (diamagnetism). By visualizing iron distribution in the brain, it is possible to identify anatomic structures that are not evident on conventional images and to evaluate various neurodegenerative diseases. It has been challenging to apply QSM in areas outside the brain because of motion artifacts from respiration and heartbeats, as well as the presence of fat, which has a different frequency to the proton. In this review, the authors provide a brief overview of the theoretical background and analyze methods of converting MRI phase images to QSM. Moreover, we provide an overview of the current clinical applications of QSM. Online supplemental material is available for this article. ©RSNA, 2022.

Discovery of Novel 3-Piperidinyl Pyridine Derivatives as Highly Potent and Selective Cholesterol 24-Hydroxylase (CH24H) Inhibitors.

Cholesterol 24-hydroxylase (CH24H or CYP46A1) is a brain-specific cytochrome P450 enzyme that metabolizes cholesterol into 24S-hydroxycholesterol (24HC) for regulating brain cholesterol homeostasis. For the development of a novel and potent CH24H inhibitor, we designed and synthesized 3,4-disubstituted pyridine derivatives using a structure-based drug design approach starting from compounds 1 (soticlestat) and 2 (thioperamide). Optimization of this series by focusing on ligand-lipophilicity efficiency value resulted in the discovery of 4-(4-methyl-1-pyrazolyl)pyridine derivative 17 (IC50 = 8.5 nM) as a potent and highly selective CH24H inhibitor. The X-ray crystal structure of CH24H in complex with compound 17 revealed a unique binding mode. Both blood-brain barrier penetration and reduction of 24HC levels (26% reduction) in the mouse brain were confirmed by oral administration of 17 at 30 mg/kg, indicating that 17 is a promising tool for the novel and selective inhibition of CH24H.

TAK-676: A Novel Stimulator of Interferon Genes (STING) Agonist Promoting Durable IFN-dependent Antitumor Immunity in Preclinical Studies.

Oncology therapies targeting the immune system have improved patient outcomes across a wide range of tumor types, but resistance due to an inadequate T-cell response in a suppressive tumor microenvironment (TME) remains a significant problem. New therapies that activate an innate immune response and relieve this suppression may be beneficial to overcome this hurdle. TAK-676 is a synthetic novel stimulator of interferon genes (STING) agonist designed for intravenous administration. Here we demonstrate that TAK-676 dose-dependently triggers activation of the STING signaling pathway and activation of type I interferons. Furthermore, we show that TAK-676 is a highly potent modulator of both the innate and adaptive immune system and that it promotes the activation of dendritic cells, natural killer cells, and T cells in preclinical models. In syngeneic murine tumor models in vivo, TAK-676 induces dose-dependent cytokine responses and increases the activation and proliferation of immune cells within the TME and tumor-associated lymphoid tissue. We also demonstrate that TAK-676 dosing results in significant STING-dependent antitumor activity, including complete regressions and durable memory T-cell immunity. We show that TAK-676 is well tolerated, exhibits dose-proportional pharmacokinetics in plasma, and exhibits higher exposure in tumor. The intravenous administration of TAK-676 provides potential treatment benefit in a broad range of tumor types. Further study of TAK-676 in first-in-human phase I trials is ongoing. Significance: TAK-676 is a novel systemic STING agonist demonstrating robust activation of innate and adaptive immune activity resulting in durable antitumor responses within multiple syngeneic tumor models. Clinical investigation of TAK-676 is ongoing.

Quantitative Susceptibility Mapping versus R2*-based Histogram Analysis for Evaluating Liver Fibrosis: Preliminary Results.

PURPOSE: The staging of liver fibrosis is clinically important, and a less invasive method is preferred. Quantitative susceptibility mapping (QSM) has shown a great potential in estimating liver fibrosis in addition to R2* relaxometry. However, few studies have compared QSM analysis and liver fibrosis. We aimed to evaluate the feasibility of estimating liver fibrosis by using QSM and R2*-based histogram analyses by comparing it with ultrasound-based transient elastography and the stage of histologic fibrosis. METHODS: Fourteen patients with liver disease were enrolled. Data sets of multi-echo gradient echo sequence with breath-holding were acquired on a 3-Tesla scanner. QSM and R2* were reconstructed by water-fat separation method, and ROIs were analyzed for these images. Quantitative parameters with histogram features (mean, variance, skewness, kurtosis, and 1st, 10th, 50th, 90th, and 99th percentiles) were extracted. These data were compared with the elasticity measured by ultrasound transient elastography and histological stage of liver fibrosis (F0 to F4, based on the new Inuyama classification) determined by biopsy or hepatectomy. The correlation of histogram parameters with intrahepatic elasticity and histologically confirmed fibrosis stage was examined. Texture parameters were compared between subgroups divided according to fibrosis stage. Receiver operating characteristic (ROC) analysis was also performed. P < 0.05 indicated statistical significance. RESULTS: The six histogram parameters of both QSM and R2*were significantly correlated with intrahepatic elasticity. In particular, three parameters (variance, percentiles [90th and 99th]) of QSM showed high correlation (r = 0.818-0.844), whereas R2* parameters showed a moderate correlation with elasticity. Four parameters of QSM were significantly correlated with fibrosis stage (ρ = 0.637-0.723) and differentiated F2-4 from F0-1 fibrosis and F3-4 from F0-2 fibrosis with areas under the ROC curve of > 0.8, but those of R2* did not. CONCLUSION: QSM may serve as a promising surrogate indicator in detecting liver fibrosis.

A case of early gastric cancer with a single giant lymph node metastasis.

BACKGROUND: Early gastric cancer (EGC) is often associated with lymphatic metastasis, but it is extremely rare to be found as a single giant lymph node. Cancer often becomes more malignant in metastatic lesions than in primary lesions, and retrodifferentiation to the fetal gastrointestinal tract during the metastatic process has been reported in gastric cancer. We report an extremely rare case of EGC with a 13-cm giant lymph node metastasis in which an adenocarcinoma with enteroblastic differentiation and yolk sac tumor-like components was observed. CASE PRESENTATION: The case was a 70-year-old man who visited his local doctor with right hypochondrial pain, which was identified by computed tomography (CT) as a giant mass. Upper endoscopy revealed a 30-mm-sized 0-IIc lesion in the greater curvature of the angular incisure and a 15-mm-sized 0-IIa lesion in the anterior wall of the lower body of the gastric body. Endoscopic biopsy revealed tubular adenocarcinoma in both lesions. The gastric lesion and the giant tumor were clinically regarded as independent lesions (gastrointestinal stromal tumor, [GIST], and EGCs), and distal gastrectomy and D1 + dissection were performed to comprehensively treat all lesions. Pathological examination revealed that the giant tumor was tubular adenocarcinoma with an intestinal phenotype and was considered a lymph node metastasis of EGCs. To exclude the possibility of metastasis of adenocarcinoma other than EGCs, postoperative positron emission tomography-computed tomography (PET-CT) and colonoscopy were performed; however, no primary site other than the stomach was found. Metastatic lymph nodes have an increased degree of atypia compared with the primary tumor, and yolk sac tumor-like carcinoma morphology was observed along with α-fetoprotein (AFP) and Spalt-like 4 (SALL4) expression in this case. It was considered that retrodifferentiation to a fetal phenotype occurred during the metastatic process. Liver metastasis occurred 6 months after surgery, and chemotherapy is currently being introduced. CONCLUSIONS: We experienced a case of EGC with a single giant lymph node metastasis. Retrodifferentiation to the fetal gastrointestinal tract during metastasis was speculated to be involved in the formation of giant lymph node metastasis and liver metastasis in this case.

Value of the CRP-albumin ratio in patients with resectable pancreatic cancer.

Background : The C-reactive protein (CRP)-albumin ratio (CAR) was reported as a prognostic factor of resectable hepatocellular carcinoma. The aim of this study was to analyse the significance of CAR in resectable pancreatic cancer. Patients and Methods : 163 patients with curative resection for pancreatic cancer were enrolled in this retrospective study. Cases of non-curative resection were excluded. The CAR was calculated with the preoperative plasma CRP and albumin values, with a cut-off value of 0.06, as calculated in a previous report. Results : Patients in the low CAR group had significantly better overall survival (OS) and disease-free survival (DFS) compared with the high CAR group (P < 0.05). On multivariate analysis, for high CAR, CA19-9 > 300 U / ml and receipt of adjuvant chemotherapy were independent risk factors for OS and DFS. High CAR was significantly associated with advanced T stage. Conclusion : The CAR might be a prognostic factor for patients with resectable pancreatic cancer. J. Med. Invest. 68 : 244-248, August, 2021.

Value of the fibrinogen-platelet ratio in patients with resectable pancreatic cancer.

Background : Several prognostic factors were reported in pancreatic cancer. The fibrinogen-platelet ratio (FPR) was reported as a prognostic factor of resectable gastric cancer. In this report, the FPR was evaluated in patients with resectable pancreatic cancer. Methods : Between 2004 and 2019, 163 patients with curative resection for pancreatic cancer were enrolled. Cases of non-curative resection were excluded. The FPR was calculated using the preoperative plasma fibrinogen and the platelet counts and the cut-off value was determined by receiver operating characteristic (ROC) curve analysis. The patients were divided into high and low FPR groups according to this cut-off value. Results : The cut-off value of FPR was 25.2. Among age, sex, body mass index (BMI), and surgical factors including surgery type, volume of blood loss and surgery time, there was no significant difference between the two groups. Patients in the low FPR group had significantly better overall survival (OS) and relapse-free survival (RFS) compared with the high FPR group (P < 0.05). On multivariate analysis, a high FPR, CA19-9 > 300 U / ml, and receipt of adjuvant chemotherapy were independent risk factors for OS and DFS. Conclusions : The FPR might be a prognostic factor for patients with resectable pancreatic cancer. J. Med. Invest. 68 : 342-346, August, 2021.

Discovery of Soticlestat, a Potent and Selective Inhibitor for Cholesterol 24-Hydroxylase (CH24H).

Cholesterol 24-hydroxylase (CH24H, CYP46A1), a brain-specific cytochrome P450 (CYP) family enzyme, plays a role in the homeostasis of brain cholesterol by converting cholesterol to 24S-hydroxycholesterol (24HC). Despite a wide range of potential of CH24H as a drug target, no potent and selective inhibitors have been identified. Here, we report on the structure-based drug design (SBDD) of novel 4-arylpyridine derivatives based on the X-ray co-crystal structure of hit derivative 1b. Optimization of 4-arylpyridine derivatives led us to identify 3v ((4-benzyl-4-hydroxypiperidin-1-yl)(2,4'-bipyridin-3-yl)methanone, IC50 = 7.4 nM) as a highly potent, selective, and brain-penetrant CH24H inhibitor. Following oral administration to mice, 3v resulted in a dose-dependent reduction of 24HC levels in the brain (1, 3, and 10 mg/kg). Compound 3v (soticlestat, also known as TAK-935) is currently under clinical investigation for the treatment of Dravet syndrome and Lennox-Gastaut syndrome as a novel drug class for epilepsies.

Prognostic prediction of resectable colorectal liver metastasis using the apparent diffusion coefficient from diffusion-weighted magnetic resonance imaging.

AIM: Diffusion-weighted magnetic resonance imaging (DWI-MRI) is used to predict tumor malignancy. Here we explored the role of apparent diffusion coefficient (ADC) values in the treatment of patients with resectable colorectal liver metastasis (CRLM). METHODS: Magnetic resonance imaging (MRI) scans were conducted using a Signa HDe or Signa Explorer 1.5-T scanner (GE Healthcare). ADC maps were calculated using DWI with b values of 0, 20, and 800 s/mm2. We enrolled 60 patients who underwent upfront hepatic resection for CRLM and divided them into ADC-high (n = 30) and ADC-low (n = 30) groups. Clinicopathological variables of the groups were compared. Immunohistochemical analysis of HIF-1α expression in tumor tissues was performed, and the relationship between the ADC value and HIF-1α expression was evaluated. RESULTS: The disease-free survival rate of the ADC-low group was significantly lower than that of the ADC-high group (P < .05). Univariate analysis revealed that tumor number (more than five), synchronous metastasis, and low ADC were prognostic factors. Multivariate analysis identified low ADC as an independent prognostic factor. Furthermore, the ADC-low group more frequently expressed high levels of HIF-1α than the ADC-high group. CONCLUSION: Low ADC values were an independent prognostic factor of resectable CRLM and correlated with HIF-1α expression.

Advantages of the Left-handed Ultrasonic Shears Technique for Robotic Gastrectomy.

PURPOSE: The aim of this study was to investigate advantages of the left-handed ultrasonic shears technique in robotic gastrectomy for gastric cancer. METHODS: We retrospectively analyzed 67 consecutive gastric cancer patients who underwent robotic gastrectomy. Fifty-six patients underwent gastrectomy with the left-handed ultrasonic shears technique (the left hand group), and 11 patients underwent surgery with the conventional approach (the conventional group). Intraoperative and postoperative outcomes were compared between the 2 groups. RESULTS: Operative blood loss, morbidity, and mortality were similar between the 2 groups. We observed a trend toward a shorter operation time and higher number of retrieved lymph nodes in the left hand group compared with the conventional group. Console time (docking-gastrectomy) in the left hand group was significantly shorter than in the conventional group (192.20 vs. 218.36 min, P<0.05). In robotic distal gastrectomy, both operation time and console time in the left hand group were significantly shorter than in the conventional group (276.10 vs. 354.80 min, 176.43 vs. 209.20 min, P<0.05 for both). The postoperative intra-abdominal infectious complication (Clavien Dindo≥1) rate in the left hand group was significantly lower than that in the conventional group (0% vs. 20%, P<0.05). CONCLUSIONS: Use of the left-handed ultrasonic shears technique is safe and provides a technically superior operative environment with satisfactory postoperative results.

Significance of Frailty in Prognosis After Hepatectomy for Elderly Patients with Hepatocellular Carcinoma.

BACKGROUND: The concept of frailty becomes important for patients who undergo surgery in this recent aging society. The aim of this study is to investigate the frailty as a prognostic factor in elderly patients with hepatocellular carcinoma (HCC) who underwent hepatectomy. PATIENTS AND METHODS: A total of 92 patients over 75 years old who underwent hepatectomy were enrolled in this study. Frailty was defined as clinical frailty scale (CFS) ≥ 4. Patients were divided into two groups, i.e., frailty group (n = 21) and no-frailty group (n = 71), and clinicopathological features were compared between them. RESULTS: The frailty group showed significant higher PIVKA-II level and larger tumor diameter (p < 0.05). CRP level and modified Glasgow prognostic score were significantly higher in the frailty group (p < 0.05). The frailty group showed higher rate of postoperative complications of Clavien-Dindo III (p = 0.06) and longer postoperative stay (p = 0.08). Cancer-specific, overall, and disease-free survival rates were significantly worse in the frailty group (p < 0.05). Frailty was detected as an independent prognostic factor on multivariate analysis of cancer-specific survival. CONCLUSION: Frailty can estimate the prognosis of HCC patients who underwent hepatectomy.

A case with overlapping features of IgG4-related autoimmune pancreatitis, Sjögren's syndrome and anti-aminoacyl-tRNA synthetase syndrome.

A 55-year-old man who had been diagnosed with autoimmune pancreatitis five years earlier was referred to our department because of finger swelling, finger stiffness and the presence of interstitial lung disease (ILD). The patient was diagnosed with Sjögren's syndrome according to the pathological findings of minor salivary glands and positive anti-SS-A antibodies. Later, at age 58, he was hospitalised due to the exacerbation of the ILD. Serum IgG4 level was checked and was found to be elevated (417 mg/dL). After the introduction of cyclosporine in addition to the prednisolone, at age 60, the ILD disease activity stabilised. However, at age 62, fever, myalgia and mechanic's hands appeared. His serum creatine kinase level was high, and magnetic resonance imaging showed inflammatory findings of muscle. In-house ELISA clarified that his serum carried anti-PL-7 antibody among anti-aminoacyl-tRNA synthetase antibodies. This is a unique case who had overlapping features of IgG4-related autoimmune pancreatitis, Sjögren's syndrome and anti-synthetase syndrome. Although the aetiology of the complications in this patient is obscure, autoimmunity might have played a significant role in the disease conditions and prognosis of the present case with IgG4-related disease.

Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for neural hyperexcitation in mice.

Cholesterol 24-hydroxylase (CH24H) is a brain-specific enzyme that converts cholesterol into 24S-hydroxycholesterol, the primary mechanism of cholesterol catabolism in the brain. The therapeutic potential of CH24H activation has been extensively investigated, whereas the effects of CH24H inhibition remain poorly characterized. In this study, the therapeutic potential of CH24H inhibition was investigated using a newly identified small molecule, soticlestat (TAK-935/OV935). The biodistribution and target engagement of soticlestat was assessed in mice. CH24H-knockout mice showed a substantially lower level of soticlestat distribution in the brain than wild-type controls. Furthermore, brain-slice autoradiography studies demonstrated the absence of [3H]soticlestat staining in CH24H-knockout mice compared with wild-type mice, indicating a specificity of soticlestat binding to CH24H. The pharmacodynamic effects of soticlestat were characterized in a transgenic mouse model carrying mutated human amyloid precursor protein and presenilin 1 (APP/PS1-Tg). These mice, with excitatory/inhibitory imbalance and short life-span, yielded a remarkable survival benefit when bred with CH24H-knockout animals. Soticlestat lowered brain 24S-hydroxycholesterol in a dose-dependent manner and substantially reduced premature deaths of APP/PS1-Tg mice at a dose lowering brain 24S-hydroxycholesterol by approximately 50%. Furthermore, microdialysis experiments showed that soticlestat can suppress potassium-evoked extracellular glutamate elevations in the hippocampus. Taken together, these data suggest that soticlestat-mediated inhibition of CH24H may have therapeutic potential for diseases associated with neural hyperexcitation.

Prognostic prediction of apparent diffusion coefficient obtained by diffusion-weighted MRI in mass-forming intrahepatic cholangiocarcinoma.

BACKGROUND: We evaluated apparent diffusion coefficient (ADC) of diffusion-weighted image MRI as a prognostic factor for mass-forming intrahepatic cholangiocarcinoma (IHCC). METHODS: We enrolled 26 patients who had undergone hepatic resections for mass-forming-type IHCC in this study, and calculated their mean ADC, using diffusion-weighted image MRI (b: 0, 20, 800 seconds/mm2 ; 1.5 T MRI). Patients were divided into the ADCHigh and the ADCLow groups at the median ADC value (n = 13 for both). We also immunohistochemically evaluated hypoxia-inducible factor (HIF)-1α in tumor tissue. RESULTS: Median age in the ADCLow was older (P = .03), and showed significant higher rate of scirrhous tumor (P = .02). The 5-year overall survival rate in the ADCLow group was significantly worse than in the ADCHigh group (P = .04). In multivariate analysis, hilar tumor, portal vein invasion and low ADC were independent prognostic factors (P < .05). The ADCLow group also had a higher rate of high HIF-1α expression than the ADCHigh group (P < .05). Representative case of ADCLow group showed rich stroma and high HIF-1α expression. CONCLUSIONS: The ADC values in MRIs can predict IHCC prognosis, and correlated with stromal density and HIF-1α expression.